Saturday, April 20, 2019

In March 2018, CMS finalized a National Coverage Determination on Next Generation Sequencing when used in cancer patients. Although the effective part of the NCD is just a few sentences out of the 80-page total text, those several sentences have powerful implications for the development of cancer care and precision medicine as a whole.

This essay highlights two key issues.

On-Label Uses of NGS Testing

First, there are already examples where the NCD for NGS blocks use of on-label FDA-approved testing for drug management.

These include blocking use of Her-2 genomics for on-label adjuvant therapy in breast cancer with on-label uses of Herceptin and related drugs. Another problem area is on-label, on-guideline use of leukemia/lymphoma chemotherapy (or decisions for bone marrow transplant), when NGS platforms are used for minimal residual disease detection.

These blockades - which will multiply with time on a rolling basis - are not seen in the proposed NCD for CAR-T therapy, which allows coverage for FDA-approved uses and on a future basis for NCCN-endorsed uses of CAR-T as they appear.

Validated Platform Transition to NGS Platforms

The second key issue is blocking the transition of tests that are approved on one platform, from use with equivalent or better results on a new platform (NGS).

For example, Agilent and others now have high-efficiency, accurate RNASeq platforms that many qRNA MAAA tests could transition to (see example here and here). However, if the RNASeq is viewed as a form of NGS, then coverage stops as soon as the transition or bridging has been fully validated. Various classes of precision medicine oncology test, including FISH and IHC, become more accurate when translated to NGS platforms (see Lin et al. 2019, here.)

Blocking these transitions is a really bad idea. It's as if NIH said, you can have this grant, but you have to use rotary-dial telephones, not push-button telephones.

Sanger (Left), NGS (Right)

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Snapshot: The NCD Rules

In the 1940s, the prolific author Isaac Asimov introduced "Three Laws of Robotics," which were very simple but led to many ramifications explored in subsequent short stories and novels. In brief, the First Law, a robot may not harm a human being. Second Law, a robot must obey orders, except when it conflicts with the first law. Third Law, a robot must protect its own existence, except not in conflict with first or second laws.

The NCD can also be summarized quickly along the same lines as Asimov's science fiction. First Law, an NGS test shall only be used in patients with recurrent or metastatic cancer. Second Law, an NGS test shall only be used once per patient. Third Law, an NGS test is covered if approved by FDA as a CDx, and also, used for an on-label patient indication, but only if it doesn't conflict with the first or second laws. Fourth Law, an NGS test may be covered by LCDs, but only if it doesn't conflict with the first or second laws.

The First Law and On-Label Uses

Here, I've extracted the coverage rules in the NCD so that the First Law is that the NGS tests shall only be used in recurrent or metastatic cancer (e.g. stage III, IV cancer). There are already examples where FDA approvals overrun this rule.

The most prominent is for Herceptin-class biologicals used as adjuvant therapy in breast cancer. The FDA has approved the Foundation Medicine test for Her-2-neu genomics, based on an FDA-validated bridging study to an FDA-approved FISH test. See here. FMI presented bridging accuracy studies in 317 blocks, 125 positive, 192 negative (various analyses, TP, FP, etc, had 80%-96% agreement). Herceptin is approved as a major adjuvant therapy for early-stage breast cancer that has, or has not, spread to lymph nodes (here). The 2017 labeling is here. Hint: That labeling is nowhere cited by the NCD.

The adjuvant studies were specifically based on gene amplification, to which the FMI labeling and approval are bridged by the FDA. Tumors were equal to (or larger than) T1c, e.g. T1 tumors in the 10-20mm range. They weren't stage 3 or 4. These fall outside the tumors allowed by the NCD's First Law requiring advanced-stage disease.

FDA labeling for the drug specifically refers to use of "FDA-approved tests" for Her-2 overexpression, thus clearly including the FMI test by reference and providing labeled uses in Stage 1-2 cancer patients.

Adding a targeted biological may improve adjuvant therapy for early-stage resected cancer, but not always (e.g. not for cetuximab and colorectal cancer, here). However, adding targeted drugs can have a substantial value for clinical outcomes in early-stage disease, including on-label uses, as shown in the case of breast cancer. And MSI-family mutations (e.g. MLH-1, MSH-2 status that are accurately diagnosed by NGS including report on the FMI test) can be used in stage 1-2 adjuvant therapy decisions (see UpToDate here; Tougeron et al. here.)

The Second Law and Multiple Uses

One of the most important concepts in hematopoeitic cancers is the detection of minimal residual disease. This was an early use of flow cytometry, but has migrated to molecular methods (e.g. molecular BCR-ABL with serial tests) and now to FDA-authorized NGS methods (the ClonoSEQ test, here). FDA has increasing moved towards using MRD as a fundamental outcome (here and here), but it is already universally used as a decision point for leukemia management.

Within Medicare MACs, the MolDx system covers ClonoSEQ in Medicare patients in the form of one, one-time test cycle with up to four MRD assays (A56322, here).

As more tests in more geographies migrate to NGS platforms for MRD, it is imperative the NCD be updated to allow more than one test per lifetime per patient in these leukemia and lymphoma patients. This would bring the NCD into consistency with new and constantly evolving FDA labeling for cancer care.

Platform Migration

It's easier to see what is blocked by the NCD that what is prevented from development.

With advances by Agilent and others, it's now directly possible to migrate qRNA tests (most MAAA tests) onto RNASeq platforms (here and here.) Almost the same day that the NCD was released controlling NGS test use in the US, such tests were being released with approval of European authorities (here). But the First and Second Law of the NCD block use of the tests solely because they are migrated onto NGS platforms. This may prevent tests from being migrated to more efficient, faster, or more accurate technology platforms. (Hence my example earlier, comparing rotary dial and pushbutton phones).

For example, a recent major breakthrough has been FDA-approved blood tests for rare RBC antigens, tests that are especially important in African-America and other minority populations. If such tests (example here) were migrated to NGS platforms for efficiency and cost, the NCD would make them non-covered. Or rather, they'd be non-covered in all Americans with a diagnosis of cancer, even a small skin cancer, but they would be covered in a dying patient with advanced metastatic cancer, which makes no sense.

Tests should be valued for their impact on care - when they are reasonable and necessary - not what platform they are run on.

A Note on Platforms

The NCD seems to treat NGS platforms as "a device" rather than as a tool or modality (like light, pumps, or wheels).

While there is one FDA category - for FMI-like tests - that defines Category II NGS platforms for use in tumors to give reports (510(k) reports) to physicians that are not drug-specific - most FDA sequencing test categories are not method specific. For example, FDA device category 21 CFR 866.6080 is NGS-specific, it's a 510(k) category not a CDx or a PMA category, and more importantly, many FDA sequencing test categories like 866.5940, 866.5900, 866.6100, 866.3365, are not sequencing technology specific.

NGS is no more an FDA device category than are "pumps" or "things that use light." The former includes heart pumps, bedside saline pumps, pain pumps, and so on. A bedside drug pump has no inherent medical necessity separate from what it is pumping, and an NGS platform has no inherent medical necessity (or approval path) separate from what it is sequencing (MRSA bugs, BRCA genes, KRAS, etc.) Nor are "things that use light" an FDA category - see ophthalmoscopes, colonoscopy devices, laparoscopic devices, AI retinal imaging devices, psoriasis UV therapy lights, and so on. There is no reason for an NCD on the FMI test in oncology to act so broadly as to even block the use of microbiology NGS tests in septic cancer patients, although that's how the NCD was written.

Conclusion

FDA doesn't attempt to cover all uses of "pumps" or "light" in one guidance document, nor is there one payer or CMS NCD policy written to handle "pumps" or "light." FDA doesn't remotely attempt to cover all uses of NGS testing in healthcare in any one guidance document, and CMS shouldn't try to do so in one NCD either. CMS ends up with something like the "Four Rules of NGS Testing" I've utilized here, and they quickly run into contradictions or insufficiencies. It's like trying to have "The Three Rules of Chess" - it won't ever work.

About the Author

Bruce Quinn MD PhD is an expert on health reform, innovation, and Medicare policy. He helps both large and small companies understand and overcome hurdles to commercialization, as well as craft business strategies for a changing environment. CONTACT Dr. Quinn through www.brucequinn.com. BACKGROUND: Dr. Quinn has worked in academic medicine, Accenture business strategies, and for the Medicare program. EDUCATION: Stanford MD/PhD, MIT Postdoc, Kellogg MBA.